Classifying Real-world Macroscopic Images in the Primary-Secondary Care Interface using Transfer Learning: Implications for Development of Artificial Intelligence Solutions using Non- dermoscopic Images.

BACKGROUND: Application of deep learning to diagnostic dermatology has been the subject of numerous studies, with some reporting skin lesion classification performance on curated datasets comparable to that of experienced dermatologists. Most skin disease images encountered in clinical settings are macroscopic, without dermoscopic information, and exhibit considerable variability. Further research is necessary to determine the generalisability of deep learning algorithms across populations and acquisition settings. OBJECTIVES: We assessed the extent to which deep learning can generalise to non-dermoscopic datasets acquired at the primary-secondary care interface in the National Health Service (NHS). We explored how to obtain clinically satisfactory performance on non-standardised, real-world local data without availability of large diagnostically labelled local datasets. We measured the impact of pre-training deep learning algorithms on external, public-domain datasets. METHODS: Diagnostic macroscopic image datasets were created from previous referrals from primary to secondary care. These included 2213 images referred from primary care practitioners in NHS Tayside and 1510 images from NHS Forth Valley acquired by medical photographers. Two further datasets with identical diagnostic labels were obtained from public domain sources, namely the International Skin Imaging Collaboration (ISIC) dermoscopic dataset and the SD-260 non-dermoscopic dataset. Deep learning algorithms, specifically SWIN transformers and an EfficientNets, were trained using data from each of these datasets. Algorithms were also fine-tuned on images from the NHS datasets after pre-training on different data combinations, including the larger public domain datasets. ROC curves and area under such curves (AUC) were used to assess performance. RESULTS: SWIN transformers tested on Forth Valley data had AUCs of 0.85 and 0.89 when trained on SD-260 and Forth Valley data, respectively. Training on SD-260 followed by fine-tuning of Forth Valley data gave an AUC of 0.91. Similar effects of pre-training and tuning on local data were observed using Tayside data, and EfficientNets. Pre-training on the larger dermoscopic image dataset (ISIC-2019) provided no additional benefit. CONCLUSIONS: Pre-training on public macroscopic images, followed by tuning to local data, gave promising results. Further improvements are needed to afford deployment in real clinical pathways. Larger datasets local to the target domain might be expected to yield further improved performance.

Nematode neuropeptides as transgenic nematicides.

Plant parasitic nematodes (PPNs) seriously threaten global food security. Conventionally an integrated approach to PPN management has relied heavily on carbamate, organophosphate and fumigant nematicides which are now being withdrawn over environmental health and safety concerns. This progressive withdrawal has left a significant shortcoming in our ability to manage these economically important parasites, and highlights the need for novel and robust control methods. Nematodes can assimilate exogenous peptides through retrograde transport along the chemosensory amphid neurons. Peptides can accumulate within cells of the central nerve ring and can elicit physiological effects when released to interact with receptors on adjoining cells. We have profiled bioactive neuropeptides from the neuropeptide-like protein (NLP) family of PPNs as novel nematicides, and have identified numerous discrete NLPs that negatively impact chemosensation, host invasion and stylet thrusting of the root knot nematode Meloidogyne incognita and the potato cyst nematode Globodera pallida. Transgenic secretion of these peptides from the rhizobacterium, Bacillus subtilis, and the terrestrial microalgae Chlamydomonas reinhardtii reduce tomato infection levels by up to 90% when compared with controls. These data pave the way for the exploitation of nematode neuropeptides as a novel class of plant protective nematicide, using novel non-food transgenic delivery systems which could be deployed on farmer-preferred cultivars.

Chemosensory Responses of Plant Parasitic Nematodes to Selected Phytochemicals Reveal Long-Term Habituation Traits.

Plant parasitic nematodes (PPN) are important crop pests within the global agri-sector. Critical to their success is a complex and highly sensitive chemosensory system used to locate plants by detecting host cues. In addition to this, the nematode neuronal system has evolved mechanisms to allow adaptation to a changing environment. Clearly, there is a need to better understand the host-parasite relationship and the mechanisms by which PPN successfully locate and infect host plants. Here, we demonstrate the chemotactic response of two economically important PPN species, Meloidogyne incognita and Globodera pallida to selected phytochemicals. We further reveal an adapted chemotactic response in M. incognita second-stage juveniles preexposed to ethephon (Eth), potato root diffusate (PRD), and salicylic acid (SA), and present pharmacological evidence supporting the existence of long-term habituation traits acting via serotonergic-dependent neurotransmission.

flp-32 Ligand/receptor silencing phenocopy faster plant pathogenic nematodes.

Restrictions on nematicide usage underscore the need for novel control strategies for plant pathogenic nematodes such as Globodera pallida (potato cyst nematode) that impose a significant economic burden on plant cultivation activities. The nematode neuropeptide signalling system is an attractive resource for novel control targets as it plays a critical role in sensory and motor functions. The FMRFamide-like peptides (FLPs) form the largest and most diverse family of neuropeptides in invertebrates, and are structurally conserved across nematode species, highlighting the utility of the FLPergic system as a broad-spectrum control target. flp-32 is expressed widely across nematode species. This study investigates the role of flp-32 in G. pallida and shows that: (i) Gp-flp-32 encodes the peptide AMRNALVRFamide; (ii) Gp-flp-32 is expressed in the brain and ventral nerve cord of G. pallida; (iii) migration rate increases in Gp-flp-32-silenced worms; (iv) the ability of G. pallida to infect potato plant root systems is enhanced in Gp-flp-32-silenced worms; (v) a novel putative Gp-flp-32 receptor (Gp-flp-32R) is expressed in G. pallida; and, (vi) Gp-flp-32R-silenced worms also display an increase in migration rate. This work demonstrates that Gp-flp-32 plays an intrinsic role in the modulation of locomotory behaviour in G. pallida and putatively interacts with at least one novel G-protein coupled receptor (Gp-flp-32R). This is the first functional characterisation of a parasitic nematode FLP-GPCR.

A First Report of Anguina pacificae in Ireland.

Anguina pacificae is a significant pest of Poa annua golf course greens in northern California. This study presents the first confirmed case of an A. pacificae infestation outside of North America, where the nematode's distribution is further restricted to a relatively limited coastal region. Species confirmation was made by morphometric and molecular methods and comparisons to closely related species including the European species, Anguina agropyri. The A. pacificae population detected on an Irish golf course was monitored over a 2-yr period and the life cycle compared with Californian population dynamics. A. pacificae was assessed for the potential risk of spreading to the local agricultural sector, in addition, the biosecurity risks from A. pacificae and plant parasitic nematodes in general were reviewed for northwest Europe.

Role of non-surgical therapies in the management of periocular basal cell carcinoma and squamous intra-epidermal carcinoma: a case series and review of the literature.

BACKGROUND: Basal cell carcinoma (BCC) and squamous intra-epidermal carcinoma (IEC) are the most common periocular tumours and can be associated with significant morbidity. Five percent of imiquimod cream and photodynamic therapy (PDT) are popular non-surgical treatment options but are currently not licensed for periocular use. OBJECTIVES: To review our experience with these treatments and summarize published literature (PubMed: up to September 2011). PATIENTS AND METHODS: We conducted a review of case notes for all patients with periocular BCC and IEC treated with either PDT or imiquimod, within National Health Service (NHS) Tayside, Scotland, from 1996 to 2009. RESULTS: Six of 13 and five of 12 lesions treated with imiquimod (median duration of clearance=35 months; range=24-55 months) and PDT (median duration of clearance=66 months; range=4-80 months), respectively, achieved clinical clearance. The majority of patients in our series did manage to tolerate and continue both treatments, with no significant longer-term adverse effects. CONCLUSIONS: Our limited experience along with published reports suggests that both imiquimod and PDT are effective in the treatment of periocular non-melanoma skin cancers in selected patients. However, surgical excision with margin control remains the gold standard for the treatment of periocular tumours.

Calcipotriol plus betamethasone dipropionate gel compared with its active components in the same vehicle and the vehicle alone in the treatment of psoriasis vulgaris: a randomised, parallel group, double-blind, exploratory study.

A two-compound ointment containing calcipotriol plus betamethasone dipropionate is an effective treatment for psoriasis vulgaris. The same active ingredients have now been combined in a gel formulation. Our objective was to compare the efficacy and safety of once daily treatment of the two-compound gel with the single components in the same gel vehicle and the gel vehicle alone, in patients with psoriasis vulgaris on the trunk and/or limbs. 364 patients received once daily treatment for up to 8 weeks with either the two-compound gel, the single components in the gel vehicle or the gel vehicle alone. The percentage of patients whose disease was clear or very mild and who had at least a two-step improvement in the Investigator's Global Assessment of disease severity at week 8, was significantly higher with calcipotriol plus betamethasone dipropionate (27.2%) than with betamethasone dipropionate (16.9%, p = 0.027), calcipotriol (11.4%, p = 0.006) or gel vehicle (0.0%, p < 0.001). This exploratory study showed that the two-compound gel was safe and more efficacious than its individual ingredients in the treatment of psoriasis vulgaris.

Short- and long-term safety assessment of a two-compound ointment containing calcipotriene/betamethasone dipropionate (Taclonex/Daivobet/Dovobet ointment): hypothalamic-pituitary-adrenal axis function in patients with psoriasis vulgaris.

The two-compound ointment (Taclonex/Daivobet/Dovobet ointment) combining calcipotriene 50 microg/g and betamethasone 0.5 mg/g (as dipropionate) is very effective in the treatment of psoriasis vulgaris. There is a possibility that hypothalamo-pituitary-axis (HPA) suppression may occur if the potent corticosteroid component is absorbed to a sufficient extent. The effect of the two-compound ointment on HPA axis function was assessed in two studies. Study 1 was a four-week, double-blind study which compared the effects of the two-compound ointment with betamethasone 0.5 mg/g (as dipropionate; Diprosone) ointment in 24 patients with extensive psoriasis (involving 15-30% of the body surface area). No patients receiving the two-compound ointment had HPA axis suppression. Study 2 assessed HPA axis function after four and 52 weeks in a subset of patients (n = 19) participating in a long-term safety study. Patients were treated with the two-compound ointment for the first four weeks followed by 48 weeks of treatment as needed with either 1) two-compound ointment; 2) two-compound ointment alternating with calcipotriene four-weekly or 3) calcipotriene. No patients using the two-compound ointment for all 52 weeks or alternating four-weekly with calcipotriene had HPA axis suppression.

Phage cocktail containing Podoviridae and Myoviridae bacteriophages inhibits the growth of Pectobacterium spp. under in vitro and in vivo conditions.

Globally, there is a high economic burden caused by pre- and post-harvest losses in vegetables, fruits and ornamentals due to soft rot diseases. At present, the control methods for these diseases are limited, but there is some promise in developing biological control products for use in Integrated Pest Management. This study sought to formulate a phage cocktail which would be effective against soft rot Pectobacteriaceae species affecting potato (Solanum tuberosum L.), with potential methods of application in agricultural systems, including vacuum-infiltration and soil drench, also tested. Six bacteriophages were isolated and characterized using transmission electron microscopy, and tested against a range of Pectobacterium species that cause soft rot/blackleg of potato. Isolated bacteriophages of the family Podoviridae and Myoviridae were able to control isolates of the Pectobacterium species: Pectobacterium atrosepticum and Pectobacterium carotovorum subsp. carotovorum. Genomic analysis of three Podoviridae phages did not indicate host genes transcripts or proteins encoding toxin or antibiotic resistance genes. These bacteriophages were formulated as a phage cocktail and further experiments showed high activity in vitro and in vivo to suppress Pectobacterium growth, potentially indicating their efficacy in formulation as a microbial pest control agent to use in planta.

Genomic Characterization, Formulation and Efficacy in Planta of a Siphoviridae and Podoviridae Protection Cocktail against the Bacterial Plant Pathogens Pectobacterium spp.

In the face of global human population increases, there is a need for efficacious integrated pest management strategies to improve agricultural production and increase sustainable food production. To counteract significant food loses in crop production, novel, safe and efficacious measures should be tested against bacterial pathogens. Pectobacteriaceae species are one of the causative agents of the bacterial rot of onions ultimately leading to crop losses due to ineffective control measures against these pathogens. Therefore, the aim of this study was to isolate and characterize bacteriophages which could be formulated in a cocktail and implemented in planta under natural environmental conditions. Transmission electron microscopy (TEM) and genome analysis revealed Siphoviridae and Podoviridae family bacteriophages. To test the protective effect of a formulated phage cocktail against soft rot disease, three years of field trials were performed, using three different methods of treatment application. This is the first study to show the application of a phage cocktail containing Podoviridae and Siphoviridae bacteriophages capable of protecting onions against soft rot in field conditions.

Randomized comparison of Mohs micrographic surgery and surgical excision for small nodular basal cell carcinoma: tissue-sparing outcome.

BACKGROUND: Mohs micrographic surgery (MMS) is recognized globally as the criterion standard for high-risk basal cell carcinoma (BCC). The main advantage of MMS over conventional surgery is the chance of complete tumor removal, but it is also thought, based on experience, to be tissue sparing. OBJECTIVE: To determine whether MMS leaves smaller surgical defects than standard surgery. METHODS AND MATERIALS: This was a randomized trial involving 30 patients with a clinical diagnosis of BCC. Patients were randomly assigned to MMS or standard surgery. In the standard surgery group the BCCs were excised with 4-mm margins. In the MMS group, tumors were excised with 2-mm margins and subsequent stages of MMS until the tumor was completely removed. An observer unaware of the treatment allocation calculated the defect size. The main outcome measure was defect size in mm(2). RESULTS: The median area of the surgical defects in the MMS group was 116.6 mm(2), versus 187.7 mm(2) in the standard surgery group (95% confidence interval for difference=61-126, p<.001). CONCLUSIONS: This is the first randomized trial demonstrating that MMS is a tissue-sparing treatment. TRIAL REGISTRATION: http://www.clinicaltrials.gov Identifier: NCT00571363. The authors have indicated no significant interest with commercial supporters.

The renin angiotensin system (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention.

Despite emergence of new systemic therapies, metastatic melanoma remains a challenging and often fatal form of skin cancer. The renin-angiotensin system (RAS) is a major physiological regulatory pathway controlling salt-water equilibrium, intravascular volume and blood pressure. Biological effects of the RAS are mediated by the vasoactive hormone angiotensin II (AngII) via two receptor subtypes, AT1R (encoded by AGTR1) and AT2R (encoded by AGTR2). We report decreasing expression and increasing CpG island methylation of AGTR1 in metastatic versus primary melanoma and detection in serum of methylated genomic DNA from the AGTR1 CpG island in metastatic melanoma implying that AGTR1 encodes a tumour suppressor function in melanoma. Consistent with this hypothesis, antagonism of AT1R using losartan or shRNA-mediated knockdown in melanoma cell lines expressing AGTR1 resulted in acquisition of the ability to proliferate in serum-free conditions. Conversely, ectopic expression of AGTR1 in cell lines lacking endogenous expression inhibits proliferation irrespective of the presence of AngII implying a ligand-independent suppressor function for AT1R. Treatment of melanoma cell lines expressing endogenous AT2R with either AngII or the AT2R-selective agonist Y6AII induces proliferation in serum-free conditions whereas the AT2R-specific antagonists PD123319 and EMA401 inhibit melanoma growth and angiogenesis and potentiate inhibitors of BRAF and MEK in cells with BRAF V600 mutations. Our results demonstrate that the RAS has both oncogenic and tumour suppressor functions in melanoma. Pharmacological inhibition of AT2R may provide therapeutic opportunities in melanomas expressing this receptor and AGTR1 CpG island methylation in serum may serve as a novel biomarker of metastatic melanoma.

Collagen Prolyl Hydroxylases Are Bifunctional Growth Regulators in Melanoma.

Appropriate post-translational processing of collagen requires prolyl hydroxylation, catalyzed by collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase, and is essential for normal cell function. Here we have investigated the expression, transcriptional regulation, and function of the collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase families in melanoma. We show that the collagen prolyl 3-hydroxylase family exemplified by Leprel1 and Leprel2 is subject to methylation-dependent transcriptional silencing in primary and metastatic melanoma consistent with a tumor suppressor function. In contrast, although there is transcriptional silencing of P4HA3 in a subset of melanomas, the collagen prolyl 4-hydroxylase family members P4HA1, P4HA2, and P4HA3 are often overexpressed in melanoma, expression being prognostic of worse clinical outcomes. Consistent with tumor suppressor function, ectopic expression of Leprel1 and Leprel2 inhibits melanoma proliferation, whereas P4HA2 and P4HA3 increase proliferation, and particularly invasiveness, of melanoma cells. Pharmacological inhibition with multiple selective collagen prolyl 4-hydroxylase inhibitors reduces proliferation and inhibits invasiveness of melanoma cells. Together, our data identify the collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase families as potentially important regulators of melanoma growth and invasiveness and suggest that selective inhibition of collagen prolyl 4-hydroxylase is an attractive strategy to reduce the invasive properties of melanoma cells.

flp gene disruption in a parasitic nematode reveals motor dysfunction and unusual neuronal sensitivity to RNA interference.

The potato cyst nematode Globodera pallida is a serious pest of potato crops. Nematode FMRFamide-like peptides (FLPs) are one of the most diverse neuropeptide families known, and modulate sensory and motor functions. As neuromuscular function is a well-established target for parasite control, parasitic nematode FLP signaling has significant potential in novel control strategies. In the absence of transgenic parasitic nematodes and the reported ineffectiveness of neuronal gene RNAi in Caenorhabditis elegans, nothing is known about flp function in nematode parasites. In attempts to evaluate flp function in G. pallida, we have discovered that, unlike in C. elegans, these genes are readily susceptible to RNAi. Silencing any of the five characterized G. pallida flp genes (Gp-flp-1, -6, -12, -14, or -18) incurred distinct aberrant behavioral phenotypes consistent with key roles in motor function. Further delineation of these effects revealed that double-stranded RNA exposure time (> or = 18 h) and concentration (> or = 0.1 microg/ml) were critical to the observed effects, which were reversible. G. pallida flp genes are essential to coordinated locomotory activities, do not display redundancy, and are susceptible to RNAi, paving the way for the investigation of RNAi-mediated flp gene silencing as a novel plant parasite control strategy.

A randomized parallel study to assess the safety and efficacy of two different dosing regimens of 5% imiquimod in the treatment of superficial basal cell carcinoma.

OBJECTIVES: This study was designed to compare the safety and efficacy of two cycled dosing regimens of imiquimod 5% cream for treatment of superficial basal cell carcinoma (sBCC). METHODS: Patients (n = 32) were randomized to receive one of two treatment regimens: 8 weeks of treatment with once-daily dosing for alternate weeks (R1) and 5 weeks of once-daily dosing with a 1-week interval in the middle of the course (R2). Efficacy measures were tumour clearance at weeks 19 and 52 and measures of patients' acceptability. RESULTS: Data from 30 patients (13 females), 14 on R1 and 16 on R2, were analysed. The results revealed an initial clearance rate of 64% at week 19 for R1 and 81% for R2 (95% CI for difference: -14% to 45%, p = 0.21). However, clearance rates at week 52 were significantly different: 43% for R1 and 88% for R2 (95% CI for difference: 11% to 68%, p = 0.02). There was no difference in acceptability of treatment as measured by composite median visual analogue scores at week 8. CONCLUSION: Five weeks of 5% imiquimod cream once daily with a 1-week interval was more effective but as well tolerated as the 8-week alternate week regimen for sBCC.

Narrowband UVB treatment is highly effective and causes a strong reduction in the use of steroid and other creams in psoriasis patients in clinical practice.

BACKGROUND: Narrowband NB-UVB phototherapy (NB-UVB) is an effective treatment for psoriasis, as demonstrated by clinical trials. However, due to required infrastructure and need for treatment attendance opinions on the value of offering this treatment in routine practice vary. AIMS: To provide high quality large-scale and long-term data on the efficacy of NB-UVB for psoriasis under real-world conditions in order to assist in management decisions. METHODS: The following resources were employed: (1) complete and prospectively recorded prescription drug records for a population of 420,000 marked by low demographic mobility, (2) prospectively recorded clinical treatment outcomes for all NB-UVB treatment episodes occurring in the local population; (3) complete dermatology electronic treatment records of all psoriasis patients, allowing cross-validation of diagnoses and treatment records. Using these data sets, we analysed all first-ever initial NB-UVB treatment episodes occurring over 79 months (n = 1749) for both clinical outcomes and the effect of NB-UVB on the use of topical treatments for psoriasis. RESULTS: Around 75% of patients both achieved a status of "clear/minimal disease" and used fewer topical treatments. NB-UVB treatment led to a strong reduction for both steroid creams (25%) and psoriasis-specific topicals, e.g. vitamin-D products (30%) during the 12-month period following NB-UVB treatment. The effects measured were specific as no effect of NB-UVB was noted on drug prescriptions unrelated to psoriasis. Results were independent of individuals administering and/or scoring treatment, as they were highly similar between four geographically separate locations. CONCLUSIONS: NB-UVB treatment is highly effective and leads to a remarkable reduction in the need for topical cream treatments for a period of at least 12 months.

A randomized, investigator-masked clinical evaluation of the efficacy and safety of clobetasol propionate 0.05% shampoo and tar blend 1% shampoo in the treatment of moderate to severe scalp psoriasis.

The clinical benefit of currently available tar blend shampoos for the treatment of scalp psoriasis is restricted due to their limited efficacy, low cosmetic appeal and potential for carcinogenicity. This 4-week multicentre, randomized, parallel-group, investigator-masked study included 162 subjects and aimed to compare the efficacy, safety and cosmetic acceptability of clobetasol propionate 0.05% shampoo versus a currently marketed tar blend 1% shampoo in subjects with moderate to severe scalp psoriasis. Clobetasol propionate shampoo was superior to tar blend shampoo with respect to all efficacy variables tested (p<0.001): Total and Global Severity Score; erythema; plaque thickening; desquamation; pruritus; total scalp area involved; and the subject's global assessment of clinical improvement. Both treatments were safe and well-tolerated. Furthermore, more subjects indicated that clobetasol propionate shampoo was more cosmetically acceptable than tar blend shampoo. Clobetasol propionate 0.05% shampoo is a good alternative to tar blend shampoo in the treatment of moderate to severe scalp psoriasis.

Exogenous RNA interference exposes contrasting roles for sugar exudation in host-finding by plant pathogens.

Plant parasitic nematodes (PPN) locate host plants by following concentration gradients of root exudate chemicals in the soil. We present a simple method for RNA interference (RNAi)-induced knockdown of genes in tomato seedling roots, facilitating the study of root exudate composition, and PPN responses. Knockdown of sugar transporter genes, STP1 and STP2, in tomato seedlings triggered corresponding reductions of glucose and fructose, but not xylose, in collected root exudate. This corresponded directly with reduced infectivity and stylet thrusting of the promiscuous PPN Meloidogyne incognita, however we observed no impact on the infectivity or stylet thrusting of the selective Solanaceae PPN Globodera pallida. This approach can underpin future efforts to understand the early stages of plant-pathogen interactions in tomato and potentially other crop plants.